The accumulation of misfolded protein aggregates is a common feature of numerous neurodegenerative disorders including Alzheimer disease (AD). Here, we examined the effects of different assembly states of amyloid beta (Abeta) on proteasome function. We find that Abeta oligomers, but not monomers, inhibit the proteasome in vitro. In young 3xTg-AD mice, we observed impaired proteasome activity that correlates with the detection of intraneuronal Abeta oligomers. Blocking proteasome function in pre-pathological 3xTg-AD mice with specific inhibitors causes a marked increase in Abeta and tau accumulation, highlighting the adverse consequences of impaired proteasome activity for AD. Lastly, we show that Abeta immunotherapy in the 3xTg-AD mice reduces Abeta oligomers and reverses the deficits in proteasome activity. Taken together, our results indicate that Abeta oligomers impair proteasome activity, contributing to the age-related pathological accumulation of Abeta and tau. These findings provide further evidence that the proteasome represents a viable target for therapeutic intervention in AD.